Current understanding of human B cell function is based upon the in vitro use of polyclonal activators, particularly pokeweed mitogen (PWM), to trigger B cell differentiation. Unfortunately, this T cell-dependent mitogen successfully induces the terminal differentiation of only a very small subset of recently activated B lymphocytes from the recirculating pool. The majority population of small resting B cells have therefore not been adequately studied, since, although these cells can be triggered to proliferate in response to B cell growth factors, they are refractory to B cell differentiation factors. The successful induction of the terminal differentiation of this hitherto unstudied major lymphocyte population has recently been reported by others and ourselves. We generated an alloreactive helper T cell clone which was capable of promoting the differentiation of small resting B cells to immunoglobulin-secreting cells at high frequency. We have data to suggest that the membrane activation signal provided by B cell by interaction with the helper T cell clone involves the Ia (class II MHC) antigen present on the B cell surface and that potentiators of intracellular cAMP may substitute for this Ia-mediated phenomenon. In light of two recent reports that retinoic acid (RA) may augment B cell differentiation by acting directly on the responsive B cell population, we propose to study the effect of this vitamin-A derivative upon human B cell responsiveness in the established differentiation assays in our laboratory, and to examine whether RA effects upon B cells may be linked to membrane- dependent activation steps, or to measurable changes in intracellular cAMP.